The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

OBJECTIVEAntigen-presenting cells such as monocytes and dendritic cells (DCs) stimulate T-cell proliferation and activation during adaptive immunity. This cellular interaction plays a role in the growth of atherosclerotic plaques. Tanshinone II A (TSN) had been shown to decrease the growth of atherosclerotic lesions. We therefore investigated the ability of TSN to inhibit human monocyte-derived DCs and their T-cellstimulatory capacity.

METHODSDCs derived from human monocytes cultured with recombinant human interleukin (IL)-4 and recombinant human granulocyte-macrophage colony-stimulating factor were co-cultured with TSN and lipopolysaccharide for 48 h. Phosphate-buffered saline was used as a negative control. Activation markers and the capacity of DCs for endocytosis were measured by flow cytometry, and proinflammatory cytokines were measured by enzyme-linked immunosorbent assays. DCs were co-cultured with lymphocytes to measure T-cell proliferation and IL-2 secretion by mixed lymphocyte reactions.

RESULTSTSN dose-dependently attenuated DC expression of costimulatory molecules (CD86), and decreased expression of major histocompatibility complex class II (human loukocyte antigen-DR) and adhesion molecules (CD54). Moreover, TSN reduced secretion of the proinflammatory cytokines IL-12 and IL-1 by human DCs, and restored the capacity for endocytosis. Finally, TSN-preincubated DCs showed a reduced capacity to stimulate T-cell proliferation and cytokine secretion.

CONCLUSIONSTSN inhibits DC maturation and decreases the expression of proinflammatory cytokines, while impairing their capacity to stimulate T-cell proliferation and cytokine secretion. These effects may contribute to the influence of TSN on the progression of atherosclerotic lesions.

Antigen-Presenting Cells ; drug effects ; Atherosclerosis ; immunology ; pathology ; B7-2 Antigen ; metabolism ; Cell Membrane ; drug effects ; metabolism ; Cytokines ; secretion ; Dendritic Cells ; drug effects ; immunology ; secretion ; Diterpenes, Abietane ; pharmacology ; Endocytosis ; drug effects ; Flow Cytometry ; Humans ; Immunity, Cellular ; drug effects ; Inflammation Mediators ; metabolism ; Lymphocyte Activation ; drug effects

Inflammasomes are large multi-protein complexes that serve as a platform for caspase-1 activation, and this process induces subsequent maturation and secretion of the proinflammatory cytokines IL-1β and IL-18, as well as pyroptosis. As an important component of the innate immune system, early activation of inflammasomes in a variety of immune cell subsets can mediate inflammatory response and immunological conditions after burn injury. Here, we review the current knowledge of inflammasomes and its role in immunological and inflammatory response at the early stage of burn injury.
Apoptosis ; Burns ; immunology ; Caspase 1 ; metabolism ; Cytokines ; Humans ; Inflammasomes ; physiology ; Inflammation Mediators ; immunology ; Interleukin-18 ; immunology ; physiology ; Interleukin-1beta ; immunology ; physiology

BACKGROUND/AIMS: Increased resting energy expenditure (REE) in rheumatoid arthritis (RA) patients is thought to be caused by hypermetabolism associated with production of proinflammatory cytokines. Our aim in the present study was to explore the possible association between REE and disease activity in females with RA. METHODS: A total of 499 female RA patients were recruited to this cross-sectional study assessing REE scores on disease activity indices (the routine assessment of patient index data 3 [RAPID3], the disease activity score 28, and the clinical/simplified disease activity index [CDAI/SDAI]) and the levels of RA-associated autoantibodies (rheumatoid factor and anticyclic citrullinated peptide [anti-CCP] antibodies). Age-matched healthy female controls (n = 131) were also enrolled. RESULTS: REE did not differ between RA patients (all patients, and those in remission or not) and controls, or between RA patients in remission or not (p > 0.05 for all comparisons). Increased REE in total RA patients was associated with younger age and a higher body mass index (BMI) (p < 0.001 and p < 0.001, respectively), but not with disease activity index scores on any of RAPID3, CDAI, or SDAI. BMI was the only clinical parameter exhibiting a significant relationship with REE quartiles (Q1 to Q4; p < 0.001); none of disease duration, functional status, or anti-CCP antibody titer in RA patients was significantly related to REE, based on analysis of covariance. CONCLUSIONS: We found no association between REE and disease activity in RA patients, implying that energy metabolism in RA patients might be independent of RA-associated systemic inflammation.
Adult ; Age Factors ; Aged ; Arthritis, Rheumatoid/blood/diagnosis/*metabolism/physiopathology ; Biological Markers/blood ; Body Mass Index ; Case-Control Studies ; Cross-Sectional Studies ; *Energy Metabolism ; Female ; Humans ; Inflammation Mediators/blood ; Middle Aged ; Peptides, Cyclic/immunology ; Predictive Value of Tests ; *Rest ; Rheumatoid Factor/blood ; Severity of Illness Index

BACKGROUND/AIMS: Acute coronary syndrome (ACS) is characterized by increased inflammatory processes and endothelial activation. We investigated the association between ACS and inflammatory mediators and matrix-degrading enzymes. METHODS: We prospectively enrolled 55 consecutive patients with ACS: 25 with unstable angina (UA) and 30 with non-ST elevated myocardial infarction (NSTEMI). For comparison, 25 age- and sex-matched subjects with no significant coronary artery stenosis were included as the control group. Peripheral serum levels of interleukin (IL)-33, matrix metalloproteinase (MMP)-9, tissue inhibitor of MMP-1, and C-reactive protein (CRP) were measured on admission, and at 12, 24, 48, and 72 hours after the initial evaluation. RESULTS: Compared to serum levels in the control group, serum levels of IL-33 decreased in the NSTEMI group (p < 0.05), and levels of MMP-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 increased in the UA group (p < 0.01, p < 0.05, respectively) and NSTEMI group (p < 0.05, p < 0.05, respectively). IL-33 levels were significantly lower on admission than at 12 hours after the initial evaluation (p < 0.05). IL-33 levels were negatively correlated with MMP-9 levels (r = -0.461, p < 0.05) and CRP levels (r = -0.441, p < 0.05). CONCLUSIONS: Elevated levels of MMP-9, TIMP-1, and decreased levels of IL-33 play a role in the development and progression of ACS.
Adult ; Angina, Unstable/blood/*enzymology/*immunology ; Biological Markers/blood ; C-Reactive Protein/metabolism ; Case-Control Studies ; Disease Progression ; Female ; Humans ; Inflammation Mediators/*blood ; Interleukins/*blood ; Male ; Matrix Metalloproteinase 9/*blood ; Middle Aged ; Myocardial Infarction/blood/*enzymology/*immunology ; Time Factors ; Tissue Inhibitor of Metalloproteinase-1/*blood

Myeloid-related protein (MRP)8/MRP14 is an endogenous Toll-like receptor 4 (TLR4) ligand and is abundant in synovial fluid (SF) of rheumatoid arthritis (RA) patients. Belonging to damage-associated molecular patterns, it amplifies proinflammatory mediators and facilitates a wide range of inflammatory and autoimmune diseases. Interleukin (IL)-17-producing T-helper (Th)17 cells have a crucial role in RA pathogenesis, and IL-6 is the key factor promoting Th17 differentiation. We investigated whether the level of MRP8/MRP14 is positively associated with IL-6 and IL-17 levels in RA SF and found that MRP8/MRP14 level had a significant correlation with IL-6 and IL-17 levels in RA SF. We also observed that MRP8-induced IL-17 production by peripheral blood mononuclear cells but MRP14 did not. Upon stimulation with MRP8, IL-6 production was enhanced by RA fibroblast-like synoviocytes (FLS) and was further elevated by coculturing RA FLS with activated CD4+ T cells. Moreover, we demonstrated that MRP8-activated IL-6 production by RA FLS promoted differentiation of Th17 cells using the coculture system consisting of CD4+ T cells and RA FLS. In addition, IL-6 blockade attenuated Th17 polarization of CD4+ T cells in the cocultures. Inhibitor studies revealed that MRP8 increased IL-6 production in RA FLS via TLR4/phosphoinositide 3-kinase/nuclear factor-kappaB and mitogen-activated protein kinase signaling pathways. Our results show that MRP8 has a crucial role in stimulating IL-6 expression by RA FLS, and subsequently promotes Th17 differentiation in RA, suggesting that neutralizing MRP8 level in RA synovium may be an effective therapeutic strategy in RA treatment.
ATP-Binding Cassette Transporters/*metabolism ; Adult ; Aged ; Arthritis, Rheumatoid/*pathology ; CD4-Positive T-Lymphocytes/metabolism ; Calgranulin B/metabolism ; Cell Differentiation/*immunology ; Fibroblasts/*metabolism/pathology ; Humans ; Inflammation Mediators/metabolism ; Interleukin-17/metabolism ; Interleukin-6/*biosynthesis ; Middle Aged ; Signal Transduction/immunology ; Synovial Fluid/cytology ; Synovial Membrane/metabolism/pathology ; Th17 Cells/*pathology ; Toll-Like Receptor 4/metabolism ; *Up-Regulation

In order to assess the number and function of macrophages in the placenta of pregnancy complicated with gestational diabetes mellitus (GDM) as well as those of normal pregnancies, placenta samples were collected from 15 GDM patients (GDM group) and 10 normal pregnant women (control group). The expression levels of macrophage markers (CD68/CD14) and inflammatory cytokines (IL-6/TNF-α) in placenta were detected using immunohistochemistry and PCR. The results showed that the number of CD68+ or CD14+ cells in the GMD group was remarkably higher than that in the control group (P<0.05), indicating that the number of macrophages in the GDM group was significantly greater than that in the control group. The mRNA expression levels of CD68+, IL-6 and TNF-α were higher in the GMD group than in the control group. In conclusion, more macrophages accumulate in placenta of pregnancy complicated with GDM, and the expression levels of pro-inflammation factors are also increased in GDM pregnancies, suggesting that macrophages and inflammatory mediators (IL-6 and TNF-α) may play an important role in GDM.
Adult ; Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; Cell Count ; Cytokines ; genetics ; immunology ; metabolism ; Diabetes, Gestational ; genetics ; immunology ; metabolism ; Female ; Humans ; Immunohistochemistry ; Inflammation Mediators ; immunology ; metabolism ; Interleukin-6 ; genetics ; immunology ; metabolism ; Lipopolysaccharide Receptors ; genetics ; metabolism ; Macrophages ; immunology ; metabolism ; pathology ; Placenta ; immunology ; metabolism ; Pregnancy ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha ; genetics ; immunology ; metabolism

OBJECTIVETo explore the correlations between serum uric acid (UA) levels and the clinical and cerebrospinal fluid (CSF) parameters of multiple sclerosis (MS).

METHODSThe medical reports of 47 MS patients admitted to Peking Union Medical College Hospital during 2008 and 2010 were reviewed. And 49 age- and gender-matched cerebral infarction patients were enrolled as control. The mean serum UA level of the MS patients was compared with that of the control group. The correlations between the UA levels and the clinical parameters including gender, disease duration, relapse rate, and disease disabilities as assessed by the Expanded Disability Status Scale score, were explored. Forty-one patients had CSF examinations. The correlations between the UA levels and the CSF parameters reflecting inflammation and tissue damage, including CSF protein, white blood cell count, oligoclonal band, 24-hour IgG index, and myelin basic protein, were also investigated.

RESULTSThe mean serum UA level in the MS patients was lower than that in the control group (247.75±52.59 µmol/L vs. 277.94±74.33 µmol/L, P=0.025) and inversely correlated with the relapse rate (P=0.049). MS patients with lower serum UA levels tended to have higher white blood cell counts and myelin basic protein level. But there was no correlation between CSF protein levels (r=0.165, P=0.273), white blood cell counts (r=-0.051, P=0.732), IgG index (r=0. 045, P=0.802), or myelin basic protein level (r=-0.248, P=0.145) and the serum UA level, respectively.

CONCLUSIONIn MS patients, UA levels might partly reflect the extent of disability and inflammation.

Adolescent ; Adult ; Aged ; Case-Control Studies ; Disease Progression ; Female ; Humans ; Inflammation ; blood ; cerebrospinal fluid ; Inflammation Mediators ; analysis ; cerebrospinal fluid ; metabolism ; Male ; Middle Aged ; Multiple Sclerosis ; blood ; cerebrospinal fluid ; immunology ; metabolism ; Spine ; Uric Acid ; blood ; Young Adult

A series of pathophysiological changes in lymph circulation system occur after severe burns. We try to elucidate the importance through summarizing our experiments on some of the changes in lymph circulation based on rat and goat lymphatic fistula model since 1998. The lymphatic contraction frequency decreased while the lymph flow speed increased during burn shock stage. Contents of several key inflammatory factors, such as TNF-alpha, IL-6, IL-8, IL-10, IL-18, and HMGB-1, were increased in lymph or lymph nodes, and they were higher than those in blood and liver. The protein concentration increased in lymph while decreased in plasma. The endotoxin was translocated to lymph earlier than to blood, therefore, the number of E. coli or the number of endotoxin translocated via lymph route were more than those via blood. The bacteria and endotoxin of pseudomonas aeruginosa could invade through local lymphatic route from infected burn wound. Th2 shift from Th1/Th2 occurred in lymph and the ratio of CD4+/CD8+ T lymph cells decreased in lymph nodes after burns, denoting local immunosuppression. The apoptosis of lymphocytes in lymph organ might contribute to this immunosuppression.
Animals ; Burns ; immunology ; metabolism ; microbiology ; CD4-CD8 Ratio ; Disease Models, Animal ; Endotoxins ; adverse effects ; Goats ; Inflammation Mediators ; immunology ; Lymphatic System ; metabolism ; Rats ; Th2 Cells ; immunology

OBJECTIVETo investigate the effect of berberine on serum levels of TNF-alpha, IL-6 and adiponectin in obese mice induced by high fat diet and its potential molecular mechanisms.

METHODNormal male Kunming mice were randomly divided into two groups taking normal chow (NC, n = 10) and high fat diet (HF, n = 30), respectively. After 13 weeks, HF mice were continuously given high fat diet and divided into three groups, model group (BM), low-dosage of berberine group (BL) and high-dosage of berberine group (BH). Mice in BL and BH were administered berberine by gavage at the dosage of 50 mg x kg(-1) and 150 mg x kg(-1), respectively. Two weeks later, oral glucose tolerance test was performed. At the end of the experiment, the mice were killed and blood samples were collected. The epididymal fat tissue and liver were removed promptly and weighed. The serum cytokine was measured by ELISA. The levels of IkappaB kinase beta (IKK-beta) and IKK-beta (ser181) were detected by Western blotting.

RESULTSerum levels of TNF-alpha, IL-6 in mice of BM were significantly higher than those in NC (P < 0.05). After two-week treatment of berberine, serum levels of TNF-alpha, IL-6 in BL and BH were lower than those in BM (P < 0.05, respectively). However, there were no significant difference of adiponectin among four groups. The degrees of phosphorylation of IKK-beta (ser181) were decreased in liver and adipose tissue in BH in comparison to that in BM, although the expression of total IKK-beta did not change. Furthermore, the glucose tolerance was improved, while the body weight and epididymal fat were reduced in mice treated with berebrine. 9: Berberine is able to reduce inflammatory cytokines expression and inhibit activation of IKK-beta (ser181) in obese mice, which may partly explain the therapeutic effect of berberine on insulin resistance and abnormal glucose metabolism.

Animals ; Berberine ; administration & dosage ; Dietary Fats ; administration & dosage ; adverse effects ; Disease Models, Animal ; Glucose Tolerance Test ; Humans ; Inflammation Mediators ; blood ; Interleukin-6 ; blood ; Liver ; drug effects ; immunology ; metabolism ; Male ; Mice ; Mice, Obese ; Obesity ; blood ; drug therapy ; immunology ; metabolism ; Signal Transduction ; drug effects ; Tumor Necrosis Factor-alpha ; blood